Empagliflozin improves diastolic function in obese ZSF1 rats by restoring the cardiac mitochondrial respiratory capacity

Abstract Background Clinical studies demonstrated beneficial effects of Sodium-Glucose-Transporter 2 inhibitors (SGLT2i) on the combined risk of cardiovascular death or heart failure hospitalization in patients with heart failure with preserved ejection fraction (HFpEF). However, underlying processes leading to cardioprotection remain unclear. Purpose The present study aimed to elucidate the impact of Empagliflozin on myocardial function and metabolism in a rat model (ZSF1 rat) with established HFpEF and to analyze underlying mechanisms. Methods 24 week old, obese ZSF1 rats were randomized either receiving standard care (obese) or Empagliflozin (Empa, 30 mg/kg/d p.o.). ZSF1 lean rats (lean) served as healthy controls. All animals underwent a baseline, intermediate and final echocardiography. After 8 weeks of treatment, hemodynamics were measured invasively, blood samples were taken, cardiac mitochondrial function was assessed and left ventricular tissue was collected for molecular and histological analyses or for transmission electron microscopy (TEM). Results Compared to the obese control Empa treated obese rats demonstrated a significantly improved diastolic function already at 4 weeks of treatment (E/é: lean: 17.9 ± 0.8; obese: 23.7 ± 0.7, p